The Colorectal Cancer Family Registry - Seattle (CCFR -S), a center within the multinational six-site Colon CFR consortium, is a population-based resource for studies of the genetics and genetic epidemiology of colorectal cancer. We are entering Phase III of this project, the largest ever cohort of colorectal cancer families. In this new application, we propose to continue to expand accrual of individuals with colorectal cancer who carry defective mismatch repair (MMR) alleles or who are at high risk of hereditary colorectal cancer due to other as-yet-unknown genetic variants. To facilitate further analyses of MMR-mutation carriers and to enable investigators to conduct more informative studies, such as those for gene mapping, in Amsterdam families who do not have evidence of an MMR defect, we will enroll families who carry an MMR or MYH mutation and families who meet the Amsterdam criteria without evidence of an MMR mutation (n=80). Probands will be recruited through a collaborative effort with the Gastrointestinal Cancer Prevention Program, an area wide high-risk clinic located at the Seattle Cancer Care Alliance, a joint Fred Hutchinson/UW/Seattle Children's facility. Eligible individuals will complete our standardized family history and risk-factor interview and provide relevant biospecimens: blood (or buccal) samples and tumor blocks. We will support the Molecular Characterization Core activities by submitting participant biospecimen samples for: screening for expression of MLH1, MSH2, and MSH6 proteins; MMR-mutation testing guided by the IHC results; MLH1 methylation testing; screening for selected mutations in MYH; and testing for somatic mutations in BRAF. We will also continue to follow up, using active and passive protocols, our large existing cohort of probands and their relatives to evaluate and monitor: risk of developing new neoplasms; recurrence of original cancer; and mortality from colorectal cancer and other causes. We are currently conducting several ancillary studies focused on: gene hunting; gene-environment interactions; screening efficacy; behavioral changes; issues related to genetic disclosure; and the economics of screening and treatment. This proposal also includes studies to characterize the colorectal lesions that have been collected to date, including germline mutations in MLH1 and MSH2 and hypermethylation of the promoter region of MLH1. The CCFR - S is also responsible for taking the lead in the administrative coordination of all Colon CFR activities, including coordination of protocols and research agendas. Relevance: In collaboration with the other five Colon CFR centers, our registry is a valuable resource for translational research in the genetic epidemiology of colorectal cancer. The CCFR - S provides an important population-based perspective within our consortium studies of colorectal cancer. [unreadable] [unreadable] [unreadable]